CN114246836A - Pregabalin sustained release tablet and preparation method thereof - Google Patents
Pregabalin sustained release tablet and preparation method thereof Download PDFInfo
- Publication number
- CN114246836A CN114246836A CN202210074776.2A CN202210074776A CN114246836A CN 114246836 A CN114246836 A CN 114246836A CN 202210074776 A CN202210074776 A CN 202210074776A CN 114246836 A CN114246836 A CN 114246836A
- Authority
- CN
- China
- Prior art keywords
- pregabalin
- polyoxyethylene
- carbomer
- release tablet
- povidone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a stable pregabalin sustained release tablet which comprises pregabalin containing an active ingredient or pharmaceutically acceptable salts or hydrates thereof, ethyl cellulose, crospovidone, polyoxyethylene, carbomer, a binder and a lubricant. The tablet has the advantages of floating performance in gastric acid medium, rapid swelling, diameter larger than 13mm, good rigidity after swelling, long-time retention in stomach, and similar release curve and various quality attributes to those of the original preparation on the market.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pregabalin sustained release tablet and a preparation method thereof.
Background
Pregabalin (Pregabalin), chemically known as (S) -3- (aminomethyl) -5-methylhexanoic acid, is a second generation calcium channel modulator that enhances affinity for the α 2- δ subunit and is involved in the endogenous inhibitory neurotransmitter γ -aminobutyric acid (GABA) associated with the modulation of brain neuronal activity, and is clinically useful in the treatment of diabetic peripheral neuropathy, post-herpetic neuralgia, and as an adjunct treatment for adult regional epileptic seizures.
The sustained-release tablet of pregabalin, which was originally developed by Pfizer and marketed in the us, can improve the patient's compliance with taking drugs, and can also reduce or avoid dose-related adverse reactions (by lowering the peak blood concentration Cmax) and improve the therapeutic effect (by increasing the time for which the effective blood concentration is maintained), compared to the immediate-release preparation of pregabalin administered 2 times or more per day, and especially to elderly patients and patients taking various drugs, and the sustained-release tablet of pregabalin is only administered once per day. However, there are some problems in developing a pregabalin dosage form that is administered once a day. Since pregabalin is absorbed through the L-amino acid delivery system, it does not show uniform gastrointestinal absorption. Clinical studies have shown that pregabalin is well absorbed in the small intestine and ascending colon, but beyond the colonic hepatic flexure, it is very poorly absorbed. This means that the average absorption window of pregabalin is 6 hours or less, and if it is developed into a general sustained-release formulation, when it is transferred to the colonic hepatic flexure after about 6 hours, these drugs will be wasted and fail to exert any effect.
According to the characteristics of the compounds of pregabalin, the original preparation selects polyvinyl acetate and polyvinylpyrrolidone as slow-release frameworks, the polyvinyl acetate is water-insoluble framework, after the tablet enters the stomach by oral administration, the size of the expanded tablet is larger than the aperture of the cardia by a swelling agent, and the framework has good floating performance and rigidity, so that the tablet can be ensured to be retained in the stomach for a long time, and the effect of slowly playing the drug effect is achieved.
Pfizer, chinese patent No. ZL200680041140.7, discloses a solid pharmaceutical composition suitable for once daily oral administration comprising pregabalin, a matrix forming agent comprising polyvinyl acetate and polyvinylpyrrolidone (povidone), the matrix forming agent being under the trade name kollidon SR, and a swelling agent comprising cross-linked polyvinylpyrrolidone, examples of which employ the powder direct compression technique.
Chinese patent number zl201510275818.9 discloses a pharmaceutical composition containing pregabalin as an active ingredient, which adopts excipients comprising a matrix forming agent and a swelling agent, wherein the matrix forming agent is a mixture of polyvinyl acetate and polyvinylpyrrolidone, the swelling agent is one of or any combination of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and polyoxyethylene, and the preparation method mentioned in the examples is a direct compression tableting and dry granulation process. The method is characterized in that a swelling agent inconsistent with the original grinding is adopted, the stability problem caused by peroxide of crosslinked polyvinylpyrrolidone is avoided, and the stability of the product is improved.
Chinese patent No. ZL201510252515.5 discloses a pregabalin gastric-floating sustained-release tablet and a preparation method thereof, wherein an excipient adopts a framework material, a swelling agent, a bleaching aid and a diluent, the framework material is selected from one or more of hydroxypropyl methylcellulose, sodium alginate and polyoxyethylene, the swelling agent is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, the bleaching aid is selected from one or more of hexadecin, octadecanol, glyceryl behenate and stearic acid, and the diluent is selected from one or more of lactose, microcrystalline cellulose, calcium hydrophosphate, mannitol and starch. The process comprises the steps of uniformly mixing a framework material, a bleaching aid and a filling agent to prepare a soft material, drying and sieving the soft material, adding pregabalin, an expanding agent and a lubricating agent, and tabletting. It features that the matrix forming agent (skeleton material) is used, but wet granulating is used, resulting in high cost.
Chinese patent application No. 202010735998.5, discloses a pregabalin gastric floating sustained release preparation, wherein the excipient adopts gel skeleton material containing alginate and swelling material containing polyoxyethylene, wherein the average molecular weight of the alginate is 1 x 104To 2X 105Polyoxyethylene having a molecular weight of 1X 105To 1X 107. It features that it uses matrix forming agent (skeleton material) inconsistent with original grinding.
Chinese patent application No. 202110604834.3 discloses a pregabalin gastric floating sustained release tablet and a preparation method thereof, wherein one or two of hydroxyethyl cellulose or ethyl cellulose (preferably hydroxyethyl cellulose) is adopted, polyoxyethylene and carbomer homopolymer A type is used as a clear hydrogel skeleton, povidone is used as a pore-forming agent, and crospovidone is used as a swelling agent. It features that it uses matrix forming agent (skeleton material) inconsistent with original grinding.
Chinese patent application No. 202110170974.4 discloses a pregabalin composition and its preparation method, firstly completely dissolving sustained-release material in solvent, and its characteristics are that the pregabalin sustained-release pellet is prepared by wet method, then adding adhesive, stirring until completely dissolving, then adding pregabalin and anti-sticking agent, stirring uniformly, then loading the drug on pellet core of base pellet to obtain pregabalin sustained-release pellet, and continuously mixing with excipient or lubricant to prepare non-tablet or capsule. The preparation method is characterized in that a blank pill core medicine feeding mode is adopted to prepare the pregabalin sustained-release pellet.
Chinese patent application No. 201810608326.0 discloses a pregabalin sustained release composition and a preparation method thereof, wherein the composition comprises an active ingredient, a matrix forming agent, a swelling agent and a gelling agent. It features that the matrix forming agent is same as the original ground product, but the swelling agent and gel agent are same as the reference preparation.
The pregabalin compounds are generally stable and their main degradation products are lactam impurities (see figure below). In summary, most of the prior art adopts polyoxyethylene or carbomer as a release retardant or a swelling agent, but the research results of the present inventors indicate that under the conditions of 40 ℃ high temperature, 60 ℃ high temperature or acceleration condition of 40 ℃/RH 75%, lactam impurities can obviously increase, for example, the impurity content at 0 moment of the original preparation is 0.45%, so that the development of a pregabalin sustained release tablet with simple preparation process, high production efficiency, good stability and good economic benefit is still needed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a stable pregabalin sustained release tablet and a preparation method thereof, the tablet has the advantages of floating performance under gastric acid medium, rapid swelling, diameter larger than 13mm, good rigidity after swelling, long-time retention in the stomach, and similar release curve and various quality attributes to those of the original preparation on the market.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a stable sustained release tablet of pregabalin comprises pregabalin or its pharmaceutically acceptable salt or hydrate, ethyl cellulose, crospovidone, polyoxyethylene, carbomer, binder and lubricant.
Preferably, the binder is selected from one or more of povidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; the lubricant is selected from one or more of magnesium stearate, talcum powder, calcium stearate, zinc stearate or sodium stearate fumarate.
Further, the amount of each component of the pregabalin sustained release tablet is as follows: 330mg of pregabalin as an active ingredient, 200mg of ethyl cellulose, 265mg of crospovidone, 180mg of polyoxyethylene, 135mg of carbomer, 20mg of a binder and 10mg of a lubricant;
or 165mg of pregabalin, 295mg of ethyl cellulose, 335mg of crospovidone, 180mg of polyoxyethylene, 135mg of carbomer, 20mg of adhesive and 10mg of lubricant.
Preferably, the viscosity of the ethyl cellulose is 10cPs, the model of the crospovidone is XL, the molecular weight of the polyoxyethylene is 6500000-7500000, and the viscosity of the carbomer is 4000cPs-10000 cPs.
Preferably, the binder is povidone K30 and the lubricant is magnesium stearate.
Preferably, the particle size of the active ingredient pregabalin is D90Is 400 to 500 μm, D10Greater than 150 μm.
The invention also aims to provide a preparation method of the stable pregabalin sustained release tablet, which adopts the following technical scheme:
a preparation method of a stable pregabalin sustained release tablet comprises the following steps:
(1) weighing and sieving: weighing polyoxyethylene, carbomer and crospovidone according to the formula ratio in sequence, and sieving with 40 mesh sieve to obtain a polyoxyethylene carbomer and crospovidone mixture; weighing ethyl cellulose with a formula ratio, and sieving the ethyl cellulose with a 24-mesh sieve; weighing pregabalin with a formula amount to pass through a 40-mesh sieve;
(2) coating an isolation layer: taking povidone K30 with the formula amount, and adding water to prepare a binder solution with the solid content of 10%; taking pregabalin with a formula amount, placing the pregabalin in a fluidized bed, and performing bottom spraying coating by using an adhesive solution to obtain a pregabalin povidone isolating layer material;
(3) mixing: sequentially adding the polyoxyethylene carbomer cross-linked povidone mixture obtained in the step (1), the pregabalin povidone isolating layer material obtained in the step (2) and the ethyl cellulose obtained in the step (1) into a mixer, and mixing;
(4) lubrication: adding magnesium stearate into the mixture obtained in the step (3), mixing, sampling and detecting the content of the intermediate;
(5) tabletting: installing the intermediate obtained in the step (4) in a mold, calculating the weight of the pressed sheet according to the content result of the intermediate, controlling the difference of the sheet weight to be +/-3%, and controlling the hardness to be 200N-240N;
(6) packaging: HPDE bottle packaging or double aluminum packaging is adopted.
Preferably, the number of revolutions of the mixer in the step (3) and the step (4) is 10 to 20 revolutions per minute.
The tablet core weight of the stable pregabalin sustained release tablet is 1133mg, active components of the pregabalin are removed, and the using amount of auxiliary materials is large, while the viscosity of the ethyl cellulose used in the tablet is 10cPs, the type of the cross-linked povidone is XL, the molecular weight of polyoxyethylene is 6500000-7500000, and the viscosity of carbomer is 4000cPs-10000 cPs; the amounts are in the ranges published by the FDA Inactive Ingredient database (Inactive Ingredient Search for applied Drug Products).
Ethyl cellulose is an excellent filler for tablets and is widely used in oral and external preparations. The ethyl cellulose has the characteristics of stable chemical property, wide dosage range and no dissolution in water and within a physiological pH range, has very similar formulation characteristics with a polyvinyl acetate povidone mixture adopted by the original preparation, has the viscosity of 10cPs and small viscosity, has small influence on the dissolution and release of the medicament, and can prolong the existence time of the tablet floating in the solution under the gelation of polyoxyethylene and carbomer.
The polyoxyethylene is polymerized by ethylene oxide under the action of a proper catalyst, and is mainly used as an adhesive, a tablet retardant and a thickening agent (a suspending agent) in the preparation. 5-85% polyoxyethylene can be used as tablet binder, the functionality of polyoxyethylene is related to molecular weight, and the high molecular weight polyoxyethylene swells through a hydrophilic skeleton to delay drug release. The polyoxyethylene adopted by the invention has the molecular weight of 6500000-7500000, has the advantages of larger molecular weight, wide dosage range, high gelation speed and good suspension property, is one of the main components for controlling the dissolution and release of the medicine, and can prolong the existence time of the tablet floating in the solution.
Carbomers are synthetic high molecular weight cross-linked polymers of acrylic acid, primarily useful as suspending agents or viscosity enhancers in liquid or semisolid pharmaceutical dosage forms, as hydrophilic gels, to modify (e.g., prolong) the drug release of the dosage form, and may be used in oral formulations, suspensions, tablets, or sustained release tablets. The carbomer adopted by the invention has the viscosity of 4000cps-10000cps, has the advantages of larger viscosity, wide dosage range, high gelling speed and good suspending ability, is one of main components for controlling the dissolution and release of the medicine, and can prolong the existence time of the tablet floating in the solution.
The crospovidone is a water-insoluble tablet disintegrating agent or a dissolving agent, can quickly show high capillary activity and excellent hydration capacity, hardly has the tendency of gelation, can be used as a swelling agent in a sustained-release preparation, and can be used as a preparation to enter the stomach to quickly absorb water and expand from gastric juice, so that the retention time of the preparation in the stomach is prolonged. The polyvinylpolypyrrolidone adopted by the invention has the model XL, has wide dosage range and good swelling property, and is one of the main components for controlling the dissolution and release of the medicine.
The adhesive used in the invention is selected from one or more of povidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; the preferred binding agent is the binding agent, preferably povidone K30, mainly used as dissolution auxiliary agent, suspending agent and tablet binding agent of solid preparation.
The method for preparing the sustained-release tablet disclosed by the invention is mainly characterized in that the active ingredient of the pregabalin is coated with the povidone K30 aqueous solution by an isolating layer, the release of the active ingredient is not influenced, the pregabalin is prevented from being directly contacted with polyoxyethylene and carbomer, and the stability of the product is greatly improved.
The pregabalin sustained release tablet does not contain a sustained release skeleton (kollidon SR) of the original developing agent, adopts ethyl cellulose as a skeleton filler, and forms a water-insoluble skeleton together with polyoxyethylene and carbomer, so that the tablet can be kept floating in a solvent for a long time; on the other hand, the invention effectively improves the stability of the product by coating the active ingredients with the isolating layer.
Drawings
FIG. 1 is a graph showing the comparison of the curves of the self-made formulation and the reference formulation in test 3 in the absence of dissolution media.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
A preparation method of a pregabalin sustained release tablet, which comprises the following steps when producing 10,00 tablets:
(1) weighing: weighing the components according to the weight ratioRaw materials and auxiliary materials, wherein the raw materials comprise 330mg of pregabalin, 200mg of ethyl cellulose, 265mg of crospovidone, 180mg of polyoxyethylene, 135mg of carbomer, povidone K3020 mg and 10mg of magnesium stearate; wherein the particle size of pregabalin adopts D90Is 4-100 μm; the particle size of the ethyl cellulose is D90Less than 50 μm. The viscosity of ethyl cellulose is 10cPs (specification is premium 10cp), the model of the cross-linked povidone is XL, the molecular weight of polyoxyethylene is 6500000-
980NF Polymer)；
(2) Sieving: weighing polyoxyethylene, carbomer and crospovidone according to the formula ratio in sequence, and sieving with 40 mesh sieve to obtain a polyoxyethylene carbomer and crospovidone mixture; weighing ethyl cellulose with a formula ratio, and sieving the ethyl cellulose with a 24-mesh sieve; weighing pregabalin with a formula amount to pass through a 40-mesh sieve;
(3) taking povidone K30 with the formula amount, and adding water to prepare a binder solution with the solid content of 10%; taking pregabalin with a formula amount, placing the pregabalin in a fluidized bed, and performing bottom spraying coating by using an adhesive solution to obtain a pregabalin povidone isolating layer material;
(4) mixing: sequentially adding the mixture of polyoxyethylene, carbomer and crospovidone in the step (1), the material of the pregabalin povidone isolating layer in the step (2) and the ethyl cellulose in the step (1) into a mixer, and mixing for 30 minutes at 15 revolutions per minute;
(5) lubrication: adding magnesium stearate into the mixture obtained in the step (3), mixing for 3 minutes at 15 revolutions per minute, and sampling to detect the content of the intermediate;
(6) tabletting: installing a 22 mm-10.8 mm oval die on the intermediate obtained in the step (4), calculating the weight of the pressed sheet according to the content result of the intermediate, controlling the difference of the sheet weight to be +/-3%, and controlling the hardness to be 200N-240N;
(7) packaging: and packaging with aluminum.
Example 2
A preparation method of a pregabalin sustained release tablet, which comprises the following steps when producing 10,00 tablets:
(1) weighing: weighing the raw materials and auxiliary materials according to the weight ratio, 165mg of pregabalin, 295mg of ethyl cellulose, 335mg of crospovidone, 180mg of polyoxyethylene, 135mg of carbomer, 20mg of adhesive and 10mg of lubricant; wherein the particle size of pregabalin adopts D90Is 4-100 μm; the particle size of the ethyl cellulose is D90Less than 50 μm. The viscosity of ethyl cellulose is 10cPs (specification is premium 10cp), the model of the cross-linked povidone is XL, the molecular weight of polyoxyethylene is 6500000-
980NF Polymer)；
(2) Sieving: weighing polyoxyethylene, carbomer and crospovidone according to the formula ratio in sequence, and sieving with 40 mesh sieve to obtain a polyoxyethylene carbomer and crospovidone mixture; weighing ethyl cellulose with a formula ratio, and sieving the ethyl cellulose with a 24-mesh sieve; weighing pregabalin with a formula amount to pass through a 40-mesh sieve;
(3) taking povidone K30 with the formula amount, and adding water to prepare a binder solution with the solid content of 10%; taking pregabalin with a formula amount, placing the pregabalin in a fluidized bed, and performing bottom spraying coating by using an adhesive solution to obtain a pregabalin povidone isolating layer material;
(4) mixing: sequentially adding the mixture of polyoxyethylene, carbomer and crospovidone in the step (1), the material of the pregabalin povidone isolating layer in the step (2) and the ethyl cellulose in the step (1) into a mixer, and mixing for 30 minutes at 15 revolutions per minute;
(5) lubrication: adding magnesium stearate into the mixture obtained in the step (3), mixing for 3 minutes at 15 revolutions per minute, and sampling to detect the content of the intermediate;
(6) tabletting: installing a 22 mm-10.8 mm oval die on the intermediate obtained in the step (4), calculating the weight of the pressed sheet according to the content result of the intermediate, controlling the difference of the sheet weight to be +/-3%, and controlling the hardness to be 200N-240N;
(7) packaging: and packaging with aluminum.
By mixing the raw and auxiliary materials in the above examples 1-2Compatibility experiments were performed. The diluent ethyl cellulose with larger dosage is prepared by the following main medicaments: and (3) auxiliary materials are 1: 5, mixing in proportion; crospovidone, polyoxyethylene and carbomer, according to the main medicines: 10 parts of auxiliary materials: 1, mixing a binding agent povidone K30 and a lubricant magnesium stearate according to the proportion of main medicaments: 20 parts of auxiliary materials: 1, respectively at high temperature (60 ℃), high humidity (90% +/-5% RH,25 ℃) and illumination (4500lx +/-500 lx,90 muW/cm) according to stability influence factor test method2) After 30 days of storage, the change of the relevant substances before and after storage was examined, and the change of appearance, content, etc. was observed. The experimental results show that the high temperature conditions: when the pregabalin and polyoxyethylene sample is placed at the high temperature of 60 ℃ for 30 days, the content is obviously reduced, and the increase of related substances is also obvious; when the pregabalin and carbomer sample is placed at the high temperature of 60 ℃ for 10 days and 30 days, related substances are obviously increased; unknown impurities can be detected when the pregabalin + film coating premix and pregabalin full-prescription samples are heated for 30 days, the total impurities are obviously increased, and the analysis is probably the situation that coating powder, polyoxyethylene and pregabalin have partial chemical reaction at 60 ℃.
The samples prepared in example 1-2 were subjected to a multi-media dissolution profile assay using a chinese pharmacopoeia dissolution apparatus 2 at 37 ℃ in a 0.06M hydrochloric acid solution, a ph4.5 buffer solution, a ph6.8 buffer solution medium, and 900 ml. The experimental result shows that the dissolution curve of the self-made preparation is similar to that of a reference preparation under different media.
Test 3
By measuring the floating time and the swelling size of the sample prepared in example 1-2: under the medium of 0.06M hydrochloric acid and 900ml, adopting a dissolution device 2 of Chinese pharmacopoeia to measure at 37 ℃. The experimental results show that the self-made preparation of the invention has better floating time and similar swelling rate than the reference preparation.
The products of the above examples 1 and 2 and the original products on the market were subjected to a study of their influence factors (40 ℃ at high temperature, 4500 + -500 lux/h light irradiation, and 75% at high humidity) for 30 days, an accelerated stability test (40 ℃/75%) for 6 months, and a long-term stability test (30 ℃/65%) for 6 months, and the properties, related substances, and contents were compared. The characteristics and the content of the self-made product at each time point are consistent with those of the product on the market in the original research, and the change trend of related substances is superior to that of the product on the market in the original research, which is shown in the following table:
the quality of the self-grinding product meets the requirements of the standard draft, and the self-grinding product is similar to the original grinding product and has good stability, and the stability of the self-preparation is superior to that of the original grinding product under various stability test conditions (such as high temperature, high humidity, illumination, acceleration and the like).
The tablet has the advantages of floating performance under gastric acid medium, rapid swelling, diameter larger than 13mm (obtained from experiment 3), good rigidity after swelling, long-time retention in stomach, and similar release curve and various quality attributes to those of the original preparation on the market.
Claims (8)
1. A stable pregabalin sustained release tablet is characterized by comprising pregabalin or pharmaceutically acceptable salts or hydrates thereof as an active ingredient, ethyl cellulose, crospovidone, polyoxyethylene, carbomer, a binder and a lubricant.
2. The stable sustained release tablet of pregabalin of claim 1, wherein the binder is selected from one or more of povidone, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose; the lubricant is selected from one or more of magnesium stearate, talcum powder, calcium stearate, zinc stearate or sodium stearate fumarate.
3. The stable pregabalin extended release tablet according to claim 1 or 2, characterized in that the amount of each component is: 330mg of pregabalin as an active ingredient, 200mg of ethyl cellulose, 265mg of crospovidone, 180mg of polyoxyethylene, 135mg of carbomer, 20mg of a binder and 10mg of a lubricant;
or 165mg of pregabalin, 295mg of ethyl cellulose, 335mg of crospovidone, 180mg of polyoxyethylene, 135mg of carbomer, 20mg of adhesive and 10mg of lubricant.
4. The stable sustained-release tablet of pregabalin of claim 3, wherein the ethylcellulose has a viscosity of 10cPs, the crospovidone type is XL, the polyoxyethylene molecular weight is 6500000-.
5. The stable sustained release tablet of pregabalin of claim 3, wherein the binder is povidone K30 and the lubricant is magnesium stearate.
6. The stable pregabalin extended release tablet according to claim 1, characterized in that the particle size of the active ingredient pregabalin adopts D90Is 400 to 500 μm, D10Greater than 150 μm.
7. The process for preparing a stable sustained-release tablet of pregabalin according to any of claims 1 to 6, characterized by comprising the steps of:
(1) weighing and sieving: weighing polyoxyethylene, carbomer and crospovidone according to the formula ratio in sequence, and sieving with 40 mesh sieve to obtain a polyoxyethylene carbomer and crospovidone mixture; weighing ethyl cellulose with a formula ratio, and sieving the ethyl cellulose with a 24-mesh sieve; weighing pregabalin with a formula amount to pass through a 40-mesh sieve;
(2) coating an isolation layer: taking povidone K30 with the formula amount, and adding water to prepare a binder solution with the solid content of 10%; taking pregabalin with a formula amount, placing the pregabalin in a fluidized bed, and performing bottom spraying coating by using an adhesive solution to obtain a pregabalin povidone isolating layer material;
(3) mixing: sequentially adding the polyoxyethylene carbomer cross-linked povidone mixture obtained in the step (1), the pregabalin povidone isolating layer material obtained in the step (2) and the ethyl cellulose obtained in the step (1) into a mixer, and mixing;
(4) lubrication: adding magnesium stearate into the mixture obtained in the step (3), mixing, sampling and detecting the content of the intermediate;
(5) tabletting: installing the intermediate obtained in the step (4) in a mold, calculating the weight of the pressed sheet according to the content result of the intermediate, controlling the difference of the sheet weight to be +/-3%, and controlling the hardness to be 200N-240N;
(6) packaging: HPDE bottle packaging or double aluminum packaging is adopted.
8. The method for preparing a pregabalin extended release tablet according to claim 7, wherein the number of revolutions of the mixer in the step (3) and the step (4) is 10 to 20 revolutions per minute.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210074776.2A CN114246836B (en) | 2022-01-21 | 2022-01-21 | Pregabalin sustained release tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210074776.2A CN114246836B (en) | 2022-01-21 | 2022-01-21 | Pregabalin sustained release tablet and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114246836A true CN114246836A (en) | 2022-03-29 |
| CN114246836B CN114246836B (en) | 2023-07-07 |
Family
ID=80799821
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210074776.2A Active CN114246836B (en) | 2022-01-21 | 2022-01-21 | Pregabalin sustained release tablet and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114246836B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150137272A (en) * | 2014-05-29 | 2015-12-09 | 일동제약주식회사 | Pregabalin sustained release tablet formulation and process |
| CN106163566A (en) * | 2014-04-07 | 2016-11-23 | 永进药品工业株式会社 | Stability-enhanced pharmaceutical composition containing Pregabalin and preparation method thereof |
| JP2018118909A (en) * | 2017-01-23 | 2018-08-02 | 株式会社三和化学研究所 | Pharmaceutical composition containing pregabalin |
| CN110585153A (en) * | 2018-06-13 | 2019-12-20 | 北京泰德制药股份有限公司 | Pregabalin sustained-release composition and preparation method thereof |
| CN111053749A (en) * | 2018-10-16 | 2020-04-24 | 北京泰德制药股份有限公司 | Pregabalin sustained-release composition and preparation method thereof |
| CN113577036A (en) * | 2021-05-31 | 2021-11-02 | 石药集团欧意药业有限公司 | Pregabalin gastric floating sustained release tablet and preparation method thereof |
-
2022
- 2022-01-21 CN CN202210074776.2A patent/CN114246836B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106163566A (en) * | 2014-04-07 | 2016-11-23 | 永进药品工业株式会社 | Stability-enhanced pharmaceutical composition containing Pregabalin and preparation method thereof |
| US20170172929A1 (en) * | 2014-04-07 | 2017-06-22 | Yungjin Pharm. Co., Ltd. | Pharmaceutical composition containing pregabalin with improved stability and method for preparing same |
| KR20150137272A (en) * | 2014-05-29 | 2015-12-09 | 일동제약주식회사 | Pregabalin sustained release tablet formulation and process |
| JP2018118909A (en) * | 2017-01-23 | 2018-08-02 | 株式会社三和化学研究所 | Pharmaceutical composition containing pregabalin |
| CN110585153A (en) * | 2018-06-13 | 2019-12-20 | 北京泰德制药股份有限公司 | Pregabalin sustained-release composition and preparation method thereof |
| CN111053749A (en) * | 2018-10-16 | 2020-04-24 | 北京泰德制药股份有限公司 | Pregabalin sustained-release composition and preparation method thereof |
| CN113577036A (en) * | 2021-05-31 | 2021-11-02 | 石药集团欧意药业有限公司 | Pregabalin gastric floating sustained release tablet and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| SHRAWANI LAMICHHANE 等: "Customized Novel Design of 3D Printed Pregabalin Tablets for Intra-Gastric Floating and Controlled Release Using Fused Deposition Modeling", 《PHARMACEUTICS》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114246836B (en) | 2023-07-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2740146C (en) | Immediate release dosage forms of sodium oxybate | |
| KR100762847B1 (en) | Multiple unit type sustained release oral formulation and process for the preparation thereof | |
| JP7148498B2 (en) | Formulation of (R)-2-amino-3-phenylpropylcarbamate | |
| EP2974720A1 (en) | Mosapride sustained-release preparation for providing pharmacological clinical effects with once-a-day administration | |
| JP2004518676A (en) | Sustained release pharmaceutical dosage form with minimized pH dependent dissolution profile | |
| EA012377B1 (en) | Solid oral pharmaceutical compositions for once daily dosing containing pregabalin, a matrix forming agent and a swelling agent | |
| JP2008509193A (en) | Sustained release pellet preparation containing pramipexole or a pharmaceutically acceptable salt thereof, its production method and use | |
| MX2010010280A (en) | Extended release forumulation containing a wax. | |
| US20050158380A1 (en) | Sustained release oral dosage forms of gabapentin | |
| JP2008528494A (en) | Pharmaceutical formulations and methods of use | |
| JP2005508331A (en) | Dosage preparation for the treatment of diabetes | |
| US20030133978A1 (en) | Pharmaceutical formulations | |
| JP2017531637A (en) | Pregabalin sustained-release preparation | |
| CN114146062A (en) | Composition and preparation method and application thereof | |
| WO2006123213A1 (en) | Modified release formulations of gliclazide | |
| WO2007080776A1 (en) | Sustained release preparation and method for production thereof | |
| JPH06316517A (en) | Sustained-release preparation | |
| CN114246836B (en) | Pregabalin sustained release tablet and preparation method thereof | |
| RU2727721C2 (en) | Sustained-release pharmaceutical composition containing rivastigmine | |
| JP2023510140A (en) | Pharmaceutical dosage forms containing cibenzoline or its salts | |
| CN112168796A (en) | Controlled-release drug sustained-release preparation of biphasic sustained-release system and preparation method thereof | |
| WO2009087675A2 (en) | Novel coated extended release pharmaceutical compositions of levetiracetam | |
| JP2009525953A (en) | Sustained release formulation of divalproic acid and its derivatives | |
| US20220354816A1 (en) | Oseltamivir formulation | |
| JPH06345649A (en) | Ipsapyrone pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230901 Address after: Room 302, Building 2, Hongyan Park, Future Research and Innovation Park, No. 138 Wuchang Avenue, Wuchang Street, Yuhang District, Hangzhou City, Zhejiang Province, 310000 Patentee after: Hangzhou Chengzhe Biopharmaceutical Co.,Ltd. Address before: 311199 floor 1, building 21, No. 535, Shunfeng Road, Linping street, Linping District, Hangzhou City, Zhejiang Province Patentee before: HANGZHOU XINNUOHUA PHARMACEUTICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right |